This is a competing renewal application for a (K0-5) Senior Scientist Award to continue interdisciplinary research on the neuroendocrine, biologic and behavioral aspects of substance abuse. I am Principal Investigator on three projects: (1) an R01 award to study the neurobiology of nicotine in men and women (DA015067); (2) a NIDA Training Grant to train young scientists in clinical and preclinical research (T32-DA07252); and (3) a NIDA contract for Phase 1 studies of pharmacotherapies for cocaine abuse and dependence (DA38836). I am also Scientific Director of a Program Project (P01-DA14528) to evaluate new strategies for medication-based treatment of cocaine abuse in clinical and preclinical studies. I am a Co-Investigator on four preclinical projects; two R01 awards for preclinical studies of the contribution of gonadal steroid hormones to the reinforcing effects of cocaine (DA14670) and of the interactions between cocaine and mu, kappa and delta opioids (DA02519) and two contracts to assess potential cocaine treatment medications in non human primates (DA7-8073) and in rats (DA0-8806). Several of these clinical and preclinical studies are concerned with the interactions between the neuroendocrine system and the reinforcing effects of cocaine and nicotine. There is increasing evidence that cocaine's abuse liability may be influenced by its stimulation of the hypothalamic-pituitary-adrenal (HPA) axis, and this in turn has suggested new approaches to treatment. The hypothalamic-pituitary-gonadal (HPG) axis is also stimulated by cocaine and preclinical studies suggest that the gonadal steroid hormones may also affect cocaine's behavioral and abuse-related effects under some conditions. We have found striking similarities between the neuroendocrine and behavioral effects of cocaine and nicotine from cigarette smoking, and both are associated with a high degree of morbidity and mortality. The increased vulnerability to infections in cocaine abusers may be associated with suppression of proinflammatory cytokines, which in turn are modulated by changes in adrenal steroid hormones. We hypothesize that interdisciplinary analysis of stimulant drug effects on the interactions between the endocrine system and immune function will clarify a fundamental aspect of the neurobiology of drug abuse and facilitate the discovery of more effective medication-based treatments. My plans for professional growth include continued study of neuroendocrinology as well as immunology. In collaboration with colleagues at the McLean Hospital Brain Imaging Center, I plan to extend our clinical studies of nicotine to explore the temporal correlates between neural activation and localization, and perturbation of the HPA and HPG axis.